EP1001802B1 - Pharmazeutisches kombinationspräparat aus parathormon und einem inhibitor der knochenresorption - Google Patents

Pharmazeutisches kombinationspräparat aus parathormon und einem inhibitor der knochenresorption Download PDF

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Publication number
EP1001802B1
EP1001802B1 EP98929965A EP98929965A EP1001802B1 EP 1001802 B1 EP1001802 B1 EP 1001802B1 EP 98929965 A EP98929965 A EP 98929965A EP 98929965 A EP98929965 A EP 98929965A EP 1001802 B1 EP1001802 B1 EP 1001802B1
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Prior art keywords
parathyroid hormone
bone
months
use according
pth
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EP98929965A
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French (fr)
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EP1001802A1 (de
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John Dietrich
Sverker Ljunghall
Sven SJÖGREN
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Shire NPS Pharmaceuticals Inc
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NPS Allelix Corp Canada
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Priority to EP04017622A priority Critical patent/EP1473040B1/de
Priority to DK04017622.4T priority patent/DK1473040T3/da
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/452—Piperidinium derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones

Definitions

  • bone is continuously subject to remodeling.
  • This is a process where bone resorption is closely linked to bone formation, through the concerted action of the bone active cells, i.e. the bone forming osteoblasts and the bone resorbing osteoclasts. These cells together form what is called a basal multicellular (metabolic) unit, or BMU.
  • the remodeling process starts with activation of the lining cells (the cells that cover the unmineralized bone).
  • the lining cells resorb the unmineralized bone, then retract and leave room for the osteoclasts which resorb the old, mineralized bone and create an environment which attracts the osteoblast to the same site.
  • the osteoblasts thereafter lay down the organic matrix, which subsequently is becoming mineralized to form new bone.
  • the resulting bone mass is thus determined by the balance between resorption by osteoclasts and formation by osteoblasts.
  • a high activation frequency increases the rate by which bone is being lost if there is a negative balance per remodeling cycle.
  • activation frequency is increased the space that is being occupied by remodeling, the remodeling space, is also increased. This will give a lowered bone mass, since a greater portion of the bone is subject to resorption as part of the remodeling process.
  • Osteoporosis is a disease which is characterized by a reduced amount of bone tissue, usually of normal composition, which has reduced strength due to a combination of low bone mass and impaired architecture, and therefore carries an increased risk of fractures.
  • osteoporosis is the result of negative bone balance per remodeling cycle, i.e. less bone is formed than is being resorbed.
  • a specific disease as responsible for the loss of bone (e.g. malabsorption of calcium and hypersecretion of corticosteroid hormones) but in the majority of patients no such disorder is identified.
  • Such patients are classified as having "primary" osteoporosis. Bone is lost with advancing age in both sexes, but in females there is generally an increased rate of loss during the first years after the menopause (hence the term "postmenopausal" osteoporosis).
  • a number of agents have been used for the prevention and treatment of bone loss and osteoporosis, e.g. estrogen, vitamin D and bisphosphonates. such as alendronate (for a review, see: Osteoporosis (Marcus, R., Feldman, D. and Kelsey, F., Eds.) Academic Press, San Diego, 1996).
  • Such agents mainly act through inhibition of bone resorption.
  • the antiresorptive agents can retard bone loss but, by definition, they do not increase bone mass within each remodeling unit. Many patients with fractures have severe bone loss at the time they come to clinical attention. Inhibition of bone resorption might not be enough to prevent fracture recurrences. Therefore it is urgent to develop therapies that can increase bone mass, i.e. anabolic agents.
  • Parathyroid hormone is an 84 amino acid polypeptide which is normally secreted from the parathyroid glands. PTH has an important physiological role to maintain serum calcium within a narrow range. Furthermore, it has anabolic properties when given intermittently. This has been well documented in a number of animal and open clinical studies, recently reviewed by Dempster, D.W. et al. (Endocrine Reviews 1993, vol. 14, 690-709). PTH has a multitude of effects on bone. Part of it is through the remodeling cycle. PTH causes both increased activation frequency and a positive balance per cycle.
  • Human PTH may be obtained through peptide synthesis or from genetically engineered yeast, bacterial or mammalian cell hosts. Synthetic human PTH is commercially available from Bachem Inc., Bubendorf, Switzerland. Production of recombinant human parathyroid hormone is disclosed in e.g. EP-B-0383751.
  • the activation frequency is doubled.
  • bone mass or bone density
  • bone mineral density is increased by 5 to 10% per year in the lumbar spine and is largely unaffected in the femoral neck, which contains a higher proportion of cortical bone.
  • the presently known methods for treatment of osteoporosis utilize bone resorption inhibition of the BMU cycle, but have the drawbacks that their onset of effect is slow and limited, and that they only cause moderate increases of bone mineral density (bone mass) and may therefore be insufficient for the treatment of patients with osteoporosis in a stage where there is high risk of recurrent fractures. Furthermore, it has not been shown that present methods can improve on the altered architecture that is a hallmark of advanced osteoporosis.
  • a method of treatment of bone metabolism disorders utilizing the order of events in the BMU cycle, and comprising administering a bone active phosphonate and, sequentially, parathyroid hormone, is disclosed in WO 96/07417 (The Procter & Gamble Company).
  • the bone active phosphonate is given for a period of greater than about 6 months, in various dosage regimens, but always prior to PTH.
  • Hodsman, A. et al. J. Bone and Mineral Research, Vol. 10, Suppl. 1, abstract No. P288, p. S200, 1995 discloses a clinical trial involving treatment with PTH for 28 days, with our without sequential calcitonin for 42 days, with this cycle repeated at 3 months intervals for 2 years. Patients were then crossed over to clodronate, 28 days per 3 months, for one year.
  • WO 97/31640 is prior art pursuant to Article 54(3) only and discloses treatment of osteoporosis by administration of anabolic agents like PTH in combination with certain estrogen agonist/antagonist.
  • EP 0792639 is prior art pursuant to Article 54(3) only and also discloses treatment of osteoporosis by administration of anabolic agents like PTH in combination with certain estrogen agonist/antagonist.
  • the anabolic agent when administered initially, i . e . as the starting point, and is then followed by administration of the resorption inhibitor, the total increase in BMD is not only maintained but also much further increased. It appears that the initial increase in activation frequency by the anabolic agent creates not only formation of new bone, but also a large remodeling space. Subsequent administration by the resorption inhibitor, inhibits further increases in the remodeling space, by decreasing the activation frequency. Upon closing, or diminishing, the existing remodeling space,
  • BMD is then allowed to increase more than was achieved during treatment with the anabolic agent alone during the first period.
  • the present invention is thus based on the concept of remodeling.
  • overriding the resorptive phase of the BMU over several consecutive cycles it fortifies the anabolic action of PTH.
  • prolonging the treatment over several BMU cycles it takes advantage of the opposite influences on the activation frequency which is increased by PTH and later reduced by bisphosphonates.
  • WO 96/07417 discloses a method of treatment of bone metabolism disorders, comprising administering a bone active phosphonate and, subsequently, parathyroid hormone.
  • the bone active phosphonate was thus given prior to PTH.
  • the order of treatment regimens provides principally different treatment responses. Slowing down the remodeling cycle with a resorption inhibitor would limit the maximum anabolic effect that can be obtained with PTH.
  • PTH is given first over several BMU cycles, not only will it enhance the BMU positive bone balance significantly, it will also increase activation frequency to such an extent that effects of subsequent antiresorptive therapy will be enhanced.
  • a bisphosphonate is given after PTH treatment, in order not only to maintain bone mass on the higher level by its antiresorptive action, but also to increase BMD by filling in the increased remodeling space through the reduction of activation frequency.
  • a BMU cycle involving activation, resorption, formation, typically takes 3 to 6 months to complete.
  • treatment with an agent that increases the activation frequency must be of sufficient duration, i.e . it must cover several BMU cycles ( e.g . 6 to 12 months). Only then can the full potential of the treatment, with regards to increases in BMD, develop.
  • the method of treatment according to the invention achieves the advantageous result that bone mass is first rapidly increased during PTH treatment and thereafter further bone mineral density is gained, compared to the results achieved with bisphosphonates alone without prior activation by PTH.
  • the present invention relates in a first aspect to the use of a combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor, said preparation being adapted for (a) the administration of parathyroid hormone during a period of approximately 6 to 24 months, preferably about 12 (or above 12) months to 24 months or about 12 (or above 12) months to 18 months, or more preferably about 18 months; and (b) after the administration of said parathyroid hormone has been terminated, the administration of a bone resorption inhibitor during a period of about 12 to 36 months or about 12 to 18 months, or more preferably about 12 months, as defined in the claims.
  • This sequence of treatments can be repeated at intervals of one to five years, until BMD has reached a value corresponding to "young normal mean".
  • the interval between treatments coincides with the period of one treatment cycle, i.e. 12 to 60 months, preferably 24 to 60 months or 24 to 42 months, or more preferably 30 to 36 months.
  • PTH parathyroid hormone
  • thyroid hormone encompasses full-length PTH(1-84) as well as PTH fragments. It will thus be understood that fragments of PTH variants, in amounts giving equivalent biological activity to PTH(1-84), can be incorporated in the formulations according to the invention, if desired. Fragments of PTH incorporate at least the amino acid residues of PTH necessary for a biological activity similar to that of intact PTH. Examples of such fragments are PTH(1-31), PTH(1-34), PTH(1-36), PTH(1-37), PTH(1-38), PTH(1-41), PTH(28-48) and PTH(25-39).
  • thyroid hormone also encompasses variants and functional analogues of PTH.
  • the present invention thus includes pharmaceutical formulations comprising such PTH variants and functional analogues, carrying modifications like substitutions, deletions, insertions, inversions or cyclisations, but nevertheless having substantially the biological activities of parathyroid hormone.
  • Stability-enhanced variants of PTH are known in the art from e.g. WO 92/11286 and WO 93/20203.
  • Variants of PTH can e.g. incorporate amino acid substitutions that improve PTH stability and half-life, such as the replacement of methionine residues at positions 8 and/or 18, and replacement of asparagine at position 16. Cyclized PTH analogues are disclosed in e.g. WO 98/05683.
  • the invention includes a preparation as described above wherein the said parathyroid hormone is selected from the group consisting of:
  • the PTH to be used in the pharmaceutical preparation according to the invention is preferably recombinant human PTH, such as full-length recombinant human PTH.
  • Parathyroid hormone can be subcutaneously administered in an amount of approximately 0.1 to 5 ⁇ g/kg body weight, preferably 0.5 to 3 ⁇ g/kg, or more preferably 1 to 2.5 ⁇ g/kg body weight.
  • nasally or pulmonary, PTH can be administered in an amount of 0.1 ⁇ g to 15 mg/kg.
  • the said bone resorption inhibitor can be a bisphosphonate, e.g. alendronate: or a substance with estrogen-like effect, e.g. estrogen; or a selective estrogen receptor modulator, e.g. calcitonin-like substance, e.g. calcitonin; or a vitamin D analog; or a calcium salt.
  • a bisphosphonate e.g. alendronate: or a substance with estrogen-like effect, e.g. estrogen; or a selective estrogen receptor modulator, e.g. calcitonin-like substance, e.g. calcitonin; or a vitamin D analog; or a calcium salt.
  • the said bone resorption inhibitor is preferably administered in an amount of 0.05 to 500 mg, preferably around 10 mg.
  • the invention provides the use of parathyroid hormone in combination with a bone resorption inhibitor in the manufacture of a medicament for the treatment or prevention of bone-related diseases, in particular osteoporosis, said medicament being adapted for (a) the administration of parathyroid hormone during a period of approximately 6 to 24 months; (b) after the administration of parathyroid hormone has been terminated, the administration of a bone resorption inhibitor during a period of approximately 12 to 36 months.
  • the parathyroid hormone and the bone resorption inhibitor are as defined above.
  • the invention provides a method of treatment or prevention of bone-related diseases, in particular osteoporosis, which comprises administering to a mammal, including man, in need of such treatment an effective amount of a pharmaceutical preparation as defined in the above. Consequently, such a method comprises administering to a mammal, including man, in need of such treatment (a) an effective amount of parathyroid hormone during a period of approximately 6 to 24 months; and (b) after the administration of parathyroid hormone has been terminated, an effective amount of a bone resorption inhibitor during a period of approximately 12 to 36 months.
  • the invention also includes a method of treatment or prevention of bone-related diseases which comprises administering, to a patient who has already been subject to treatment with parathyroid hormone during a period of approximately 6 to 24 months, after the administration of parathyroid hormone has been terminated, an effective amount of a bone resorption inhibitor during a period of approximately 12 to 36 months.

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Claims (15)

  1. Verwendung eines Parathyroidhormons in Kombination mit einem Inhibitor der Knochenresorption bei der Herstellung eines Arzneimittels zur Behandlung oder Vorbeugung von knochenbezogenen Krankheiten, wobei
    (a) eine wirksame Menge Parathyroidhormon als Startpunkt der Behandlung für einen Zeitraum von etwa 6 bis 24 Monaten verabreicht werden soll; und
    (b) nachdem die Verabreichung von Parathyroidhormon beendet worden ist, eine wirksame Menge eines Inhibitors der Knochenresorption für einen Zeitraum von 12-36 Monaten verabreicht werden soll, ,wobei der Inhibitor der Knochenresorption ausgewählt ist aus der Gruppe bestehend aus einem Bisphosphonat, Östrogen, Toremifen, einer Calcitonin-artigen Substanz, einem Vitamin-D-Analog und einem Calciumsalz.
  2. Verwendung gemäß Anspruch 1, wobei das Parathyroidhormon ausgewählt ist aus der Gruppe bestehend aus:
    (a) Volllängen-Parathyroidhormon;
    (b) biologisch aktive Variante des Volllängen-Parathyroidhonnons;
    (c) biologisch aktive Parathyroidhormonfragmente; und
    (d) biologisch aktive Varianten von Parathyroidhormonfragmenten.
  3. Verwendung gemäß Anspruch 2, wobei das biologisch aktive Parathyroidhormonfragment PTH(1-34) ist.
  4. Verwendung gemäß Anspruch 2, wobei das Parathyroidhormon Volllängen-Parathyroidhormon ist.
  5. Verwendung gemäß Anspruch 4, wobei das Parathyroidhormon etwa 18 Monate lang verabreicht werden soll.
  6. Verwendung gemäß Anspruch 4, wobei der Inhibitor der Knochenresorptibn etwa 12 bis 18 Monate lang verabreicht werden soll.
  7. Verwendung gemäß Anspruch 6, wobei der Inhibitor der Knochenresorption etwa 12 Monate lang verabreicht werden soll.
  8. Verwendung gemäß irgendeinem der Ansprüche 1 bis 7, wobei der Inhibitor der Knochenresorption ein Bisphosphonat ist.
  9. Verwendung gemäß Anspruch 8, wobei das Bisphosphonat Alendronat ist.
  10. Verwendung gemäß irgendeinem der Ansprüche 1 bis 7, wobei die Calcitoninartige Substanz Calcitonin ist.
  11. Verwendung gemäß irgendeinem der Ansprüche 1 bis 10, wobei die knochenbezogene Krankheit Osteoporose ist.
  12. Verwendung gemäß irgendeinem der Ansprüche 1 bis 11, wobei, nachdem die Verabreichung des Inhibitors der Knochenresorption beendet worden ist, weder Parathyroidhormon noch ein Inhibitor der Knochenresorption für eine Ruhephase von mindestens 12 Monaten, aber weniger als 60 Monaten, weiter verabreicht werden soll.
  13. Verwendung gemäß Anspruch 12, wobei die Ruhephase mindestens 24 Monate, aber weniger als 60 Monate ist.
  14. Verwendung gemäß Anspruch 12, wobei die Ruhephase mindestens 24 Monate, aber weniger als 42 Monate ist.
  15. Verwendung gemäß Anspruch 12, wobei die Ruhephase mindestens 30 Monate, aber weniger als 36 Monate ist.
EP98929965A 1997-06-19 1998-06-08 Pharmazeutisches kombinationspräparat aus parathormon und einem inhibitor der knochenresorption Expired - Lifetime EP1001802B1 (de)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP04017622A EP1473040B1 (de) 1997-06-19 1998-06-08 Verwendung von humanem Parathyroid-hormon
DK04017622.4T DK1473040T3 (da) 1997-06-19 1998-06-08 Anvendelse af humant parathyroidhormon

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SE9702401 1997-06-19
SE9702401A SE9702401D0 (sv) 1997-06-19 1997-06-19 Pharmaceutical use
PCT/SE1998/001095 WO1998057656A1 (en) 1997-06-19 1998-06-08 A combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor

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EP1001802A1 EP1001802A1 (de) 2000-05-24
EP1001802B1 true EP1001802B1 (de) 2004-09-08

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EP04017622A Expired - Lifetime EP1473040B1 (de) 1997-06-19 1998-06-08 Verwendung von humanem Parathyroid-hormon
EP98929965A Expired - Lifetime EP1001802B1 (de) 1997-06-19 1998-06-08 Pharmazeutisches kombinationspräparat aus parathormon und einem inhibitor der knochenresorption

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US (8) US6284730B1 (de)
EP (2) EP1473040B1 (de)
JP (3) JP4989811B2 (de)
AT (2) ATE275419T1 (de)
AU (1) AU753477B2 (de)
CA (2) CA2294101C (de)
CY (1) CY1110287T1 (de)
DE (2) DE69841279D1 (de)
DK (2) DK1001802T3 (de)
ES (2) ES2335404T3 (de)
HK (2) HK1029738A1 (de)
PT (2) PT1001802E (de)
SE (1) SE9702401D0 (de)
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CA2347330C (en) * 2001-05-10 2002-03-12 Pharmaceutical Partners Of Canada Inc. Liquid injectable formulation of disodium pamidronate
PT1397156E (pt) 2001-06-01 2007-05-31 Novartis Ag Método para a administração oral da hormona paratireóide ( pth ).
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TWI329105B (en) 2002-02-01 2010-08-21 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds and their uses
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